Chronic myelogenous leukemia (CML) is a pluripotential hematopoietic stem cell malignancy characterized by three distinct phases: chronic, accelerated, and blast crisis phases. It is classified as a myeloproliferative disorder and accounts for 15% of adult leukemia cases.
Epidemiology and Incidence Current Statistics • Annual incidence: Approximately 1 case per 100,000 population • Lifetime risk: Approximately 1 in 526 in the US • 2017 estimates: 8,950 new diagnoses expected • 2023 estimates: 8,930 new diagnoses, 1,310 deaths • Adult leukemia proportion: 14% of all new leukemias, 20% of adult leukemias • Pediatric cases: Exceedingly rare, accounts for 2-3% of childhood leukemias Demographics • Median age at presentation: 50-60 years (some sources indicate 67 years) • Age distribution: 12-30% of patients are >60 years at diagnosis • Gender/ethnic factors: No known hereditary, familial, geographic, or ethnic associations Prognosis and Survival • Pre-TKI mortality: 10% in first two years, 20-25% in subsequent years • Modern 10-year survival: >90% for newly diagnosed CML • Current mortality rate: ~2% per year for first 10 years • Life expectancy: Approaching that of healthy population with TKI treatment Pathophysiology Molecular Basis Primary genetic abnormality: Philadelphia chromosome – t(9;22)(q34;q11) present in 95% of cases Molecular mechanism: • Reciprocal translocation between chromosomes 9 and 22 • Fusion of BCR gene (chromosome 22) with ABL1 gene (chromosome 9) • Creates BCR-ABL fusion gene encoding p210(BCR-ABL) protein • Results in constitutively active tyrosine kinase enzyme • Leads to deregulated cellular proliferation and unlimited self-renewal Transcript Types • b3a2 transcript: Predominant type • e14a2 (BCR-ABL1): Associated with earlier response and better outcomes with imatinib • e13a2: Associated with poorer clinical outcomes than e14a2 Cryptic Cases 5-10% of cases have cytogenetically cryptic Philadelphia chromosome, requiring: • Fluorescence in situ hybridization (FISH) for BCR-ABL fusion detection • Polymerase chain reaction (PCR) for BCR-ABL mRNA transcript detection Risk Factors Environmental • Increased incidence in atomic bomb survivors (Japan) • Radiation exposure (radiologists, ankylosing spondylitis patients treated with radiation) Genetic Markers • Der(9) deletions: Present in 10-15% of patients, associated with unfavorable prognosis • More common in younger patients and those with anemia Clinical Presentation Disease Phases Chronic Phase (85% of presentations) • Duration: Usually lasts 3-5 years, may extend to 4-6 years • Symptoms: Up to 50% are asymptomatic at diagnosis • Bone marrow blasts: <15% • Peripheral blood blasts: <15% Accelerated Phase (15% progression rate) • Duration: May last up to 1 year • Criteria (one or more): • 15% or more blasts in peripheral blood/bone marrow • 20% or more basophils in peripheral blood • Platelet count <100,000/μL (unrelated to treatment) • Cytogenetic evolution • Bone marrow/peripheral blasts: 15-30% Blast Crisis Phase • Duration: 3-6 months • Definition: >30% blasts in bone marrow or peripheral blood • Types: • Myeloid (2/3 of cases) • Lymphoid (1/3 of cases) • Features: Acute leukemia symptoms (fever, weight loss, bleeding, anemia) Clinical Signs and Symptoms Common Presentations • Splenomegaly: Present in 46-76% of patients • Left upper quadrant pain: Due to splenomegaly • Early satiety: Related to spleen enlargement • Constitutional symptoms: Night sweats, fatigue • Anemia symptoms: Weakness, shortness of breath • Bleeding: Due to platelet dysfunction Rare Presentations • Hyperviscosity symptoms: <5% of patients when WBC >250,000/μL • Priapism: When white count exceeds 250,000/μL Laboratory Findings Characteristic Hematologic Pattern • Absolute leukocytosis with left shift • Classic “myelocyte bulge” • Blast count: Usually <2% in chronic phase • Basophilia: Nearly universal • Absolute eosinophilia: 90% of cases • Monocytosis: Present but not increased percentage • Platelet count: Normal to elevated; thrombocytopenia possible Differential Diagnosis • Chronic myelomonocytic leukemia • Atypical CML • Chronic neutrophilic leukemia • Essential thrombocytosis Diagnostic Workup Initial Assessment • History and physical examination • Spleen palpation • Complete blood count with differential • Comprehensive metabolic panel • Hepatitis B panel Definitive Diagnosis • Bone marrow aspirate and biopsy: • Morphologic evaluation • Cytogenetic analysis • Flow cytometry • Molecular studies: • Quantitative RT-PCR for BCR-ABL1 transcript • FISH for t(9;22)(q34;q11.2) • Baseline BCR-ABL1 quantification for monitoring Risk Stratification Chronic phase CML risk groups: Low, intermediate, and high Risk factors: • Patient age • Spleen size • Platelet count • Percentage of blasts, basophils, and eosinophils in peripheral blood Prognostic associations: • Higher age → increased mortality risk • Higher peripheral blasts → increased mortality risk • Larger spleen → increased mortality risk • Low platelet counts → increased mortality risk Treatment Overview Treatment Goals and Milestones Primary Goals • Complete hematologic response at 3 months • Complete cytogenetic response at 12 months • Major molecular response at 18 months Response Definitions Hematologic Response: • Normalization of WBC count • Resolution of splenomegaly Cytogenetic Response: • Complete (CCyR): 0% Philadelphia+ metaphases • Major: 0-35% Philadelphia+ metaphases • Minor: 35-90% Philadelphia+ metaphases Molecular Response (International Scale): • Major Molecular Response (MMR): BCR-ABL ≤0.1% (3-log reduction) • Deep Molecular Responses (DMR): • MR4.0: BCR-ABL <0.01% • MR4.5: BCR-ABL <0.0032% • MR5: BCR-ABL <0.001% (5-log reduction) • Complete Molecular Response: Undetectable BCR-ABL by PCR Tyrosine Kinase Inhibitor (TKI) Therapy First-Line TKIs for Chronic Phase Imatinib (Standard of Care) • Dosage: 400 mg daily (standard), 600-800 mg daily (high-dose) • IRIS Trial Results: • Complete cytogenetic response: 87% achieved at some time • 5-year progression-free survival: 83% • 5-year overall survival: 89% • Major molecular response at 12 months: 40% Efficacy Outcomes: • 75% complete cytogenetic remission at 400 mg/day • 90% complete cytogenetic remission at 800 mg/day • Overall survival at 8 years: 86% Second-Generation TKIs Dasatinib: • Dosage: 100 mg once daily • Advantages: Faster time to major molecular response (6.3 vs 9.2 months vs imatinib) • Response rates: 45% MMR vs 28% with imatinib • Complete cytogenetic response: 77% vs 66% with imatinib Nilotinib: • Dosage: 300 mg twice daily • ENESTnd Trial: Superior to imatinib for MMR (44% vs 22%) and CCyR (79% vs 65%) • Characteristics: More potent and selective than imatinib Bosutinib: • BEFORE Study: Higher 12-month MMR than imatinib • Side effects: Higher GI events and transaminase elevations Third-Generation TKIs Ponatinib (Iclusig): • Indication: Resistant/intolerant to prior TKI therapy • Special feature: Active against T315I mutation • Target population: T315I-positive patients Asciminib: • Generation: Third-generation TKI • Indication: Effective in relapsed disease • Mechanism: BCR-ABL1 inhibitor with superior efficacy and favorable safety profile TKI Selection Guidelines First-Line Selection Criteria • Low-risk patients: Generic imatinib recommended • Intermediate/high-risk patients: Dasatinib or nilotinib preferred • Young patients: Consider second-generation TKIs for higher chance of deep molecular response Comorbidity Considerations • Heart disease/arrhythmias/pancreatitis/hyperglycemia: Prefer dasatinib • Lung disease/pleural effusion risk: Prefer nilotinib Resistance and Mutations BCR-ABL Mutations • Frequency: Account for 36-48% of imatinib-resistant cases • Most common mechanism of imatinib resistance • Can occur: Before or after treatment initiation T315I “Gatekeeper” Mutation • Frequency: 5-25% of patients (higher in relapsed disease) • Resistance profile: All first and second-generation TKIs • Molecular change: Isoleucine substitution for threonine at position 315 • Treatment: Ponatinib is active against T315I Management of Resistance • Dose escalation: Imatinib 800 mg daily can overcome some resistance • TKI switching: Second-generation TKIs for imatinib failure • Mutation testing: Guide TKI selection • Omacetaxine: Can overcome T315I mutation Treatment Monitoring and Response Assessment Monitoring Schedule Methods: Hematologic, cytogenetic, and molecular assessments Early Response Predictors • 3-month BCR-ABL levels: • <10% (1-log reduction): Associated with improved long-term outcomes • 1-2 log reduction: 69% achieve MMR • 2-log reduction: 100% achieve MMR • ≤1-log reduction: Only 13% achieve MMR Response Kinetics and Outcomes • Speed of response: Critical for long-term success • Early CCyR: Associated with better overall survival • MMR by 12 months: 91% event-free survival vs 78% without MMR • Deep molecular responses: Correlated with survival and treatment discontinuation eligibility Treatment-Free Remission (TFR) Rationale • Reduce TKI-related adverse events • Minimize pharmacologic and economic burden • Prevent long-term toxicities Eligibility Criteria • Sustained deep molecular response: Usually MR4.5 for ≥2 years • Treatment duration: Minimum 3 years of TKI therapy • Risk assessment: Not recommended for higher-risk patients TFR Study Results STIM Study • Participants: 100 patients with sustained complete molecular response (>5-log reduction for ≥2 years) • Molecular relapse: 54% after median 17 months • Sustained remission: 46% remained in CMR at median 14 months • 12-month probability: 43% maintained CMR TWISTER Study • Relapse-free interval: 47% at 2 years • Re-treatment sensitivity: All patients responsive to imatinib re-introduction DASFREE Trial (Dasatinib) • 1-year TFR rate: 49% • Molecular relapse: 51% lost MMR after median 4 months • Re-treatment response: All patients regained MMR after median 2 months TFR Outcomes by TKI • Second-generation TKIs: Higher TFR rates than imatinib due to deeper molecular responses • Overall success: ~50% maintain remission at 2 years after stopping first or second-line therapy • Relapse timing: Most relapses occur within 6 months of discontinuation Advanced Phase CML Management Accelerated Phase (CML-AP) • Initial therapy: Newer generation TKIs (dasatinib or ponatinib preferred over imatinib) • Goal: Reduce CML burden • Consideration: Early allogeneic stem cell transplantation Blast Crisis (CML-BP) • Treatment approach: TKI + chemotherapy combinations • Response rates: • Nonlymphoid CML-BP: 40% • Lymphoid CML-BP: 70-80% • Median survival: • Nonlymphoid: 6-12 months • Lymphoid: 12-24 months • Optimal approach: TKI + intensive chemotherapy followed by stem cell transplantation Stem Cell Transplantation Indications • Current role: No longer first-line for chronic phase CML • Preferred candidates: Younger patients with HLA-matched donors • Timing: Within 1 year of diagnosis for optimal outcomes Outcomes • Chronic phase transplant: ~70% survival rate • Young patients (within 1 year): 50-55% 10-year survival • Blast crisis transplant: Only 6% 5-year survival • Long-term outcomes: • 10-year overall survival: 65.7% (with pre-transplant TKI) vs 73.0% (without) • 20-year CML-related mortality: 6% • 20-year non-CML-related mortality: 36% Graft-vs-Tumor Effect • Donor lymphocyte infusions: 60-80% complete remission in relapsed patients • Relapse rate: 10-20% within 3 years post-transplant Pediatric CML Epidemiology • Frequency: Exceedingly rare, 2-3% of childhood leukemias • Treatment: Imatinib effective with response rates similar to adults Response Rates in Children (12 months) • Complete hematologic response: 98% • Complete cytogenetic response: 61% • Major molecular response: 31% Adverse Effects and Safety Profile TKI-Specific Toxicities Imatinib • Common: Superficial edema, nausea, muscle cramps, rashes • Grade 3-4 non-hematologic: Musculoskeletal pain (2.7%), joint pain (2.4%), abdominal pain (2.4%) • Hematologic: Neutropenia (14.3%), thrombocytopenia (7.8%), anemia (3.1%) Second-Generation TKIs • Nilotinib: Vascular events • Dasatinib: Pulmonary hypertension, pleural effusions • Bosutinib: Mild renal effects, GI toxicity Third-Generation TKIs • Ponatinib: Vascular events (arterial thrombosis) Long-Term Considerations • Cardiovascular events: Increased risk with several TKIs • Surveillance: Regular monitoring for cardiovascular complications • Quality of life: Consider in treatment selection and TFR decisions Future Directions and Research Combination Therapies • TKI + Interferon: Better short-term results, no long-term survival benefit • TKI + Chemotherapy: Improved outcomes in blast crisis Novel Approaches • Asciminib: Promising third-generation option • Treatment optimization: Personalized medicine based on risk stratification • TFR expansion: Identifying optimal candidates and timing Biomarkers and Predictors • OCT-1 levels: Predict imatinib response (higher levels = better survival) • BCR-ABL transcript levels: Guide treatment decisions and monitoring • Molecular monitoring: Essential for treatment optimization and TFR decisions Key Clinical Pearls 1. Early response matters: BCR-ABL <10% at 3 months predicts better long-term outcomes 2. Deep molecular responses: Enable treatment discontinuation consideration 3. T315I mutation: Requires ponatinib for effective treatment 4. TFR is achievable: ~50% of selected patients maintain remission off treatment 5. Second-generation TKIs: Faster responses but no clear overall survival advantage over imatinib 6. Modern CML prognosis: Life expectancy approaching normal population 7. Monitoring is crucial: Regular molecular monitoring guides treatment decisions 8. Resistance is manageable: Multiple TKI options available for treatment failure